title: Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells.
abstract: A highly acidic environment surrounds proximal tubular cells as a result of their reabsorption of HCO(3)(-). It is unclear whether this luminal acidity affects proteinuria-induced progression of tubular cell damage. Here, we investigated the contribution of luminal acidity to superoxide (O(2)(·-)) production induced by oleic acid-bound albumin (OA-Alb) in proximal tubular cells. Acidic media significantly enhanced OA-Alb-induced O(2)(·-) production in the HK-2 proximal tubular cell line. Simultaneous treatment with both OA-Alb and acidic media led to phosphorylation of the intracellular pH sensor Pyk2. Highly phosphorylated Pyk2 associated with activation of Rac1, an essential subcomponent of NAD(P)H oxidase. Furthermore, knockdown of Pyk2 with siRNA attenuated the O(2)(·-) production induced by cotreatment with OA-Alb and acid. To assess whether luminal alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO(3) feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O(2)(·-)-induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease.
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. tomokazu-souma@med.tohoku.ac.jp
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Souma
authors.forename: Michiaki
authors.initials: M
authors.lastname: Abe
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Takai
authors.forename: Noriko
authors.initials: N
authors.lastname: Yanagisawa-Miyazawa
authors.forename: Eisuke
authors.initials: E
authors.lastname: Shibata
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Takafumi
authors.initials: T
authors.lastname: Toyohara
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanemoto
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
mesh_terms: D000418:Albumins / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D011507:Proteinuria / Q000150:complications* / Q000378:metabolism / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017693:Sodium Bicarbonate / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000418:Albumins; D017382:Reactive Oxygen Species; D019301:Oleic Acid; D017693:Sodium Bicarbonate; D019255:NADPH Oxidases; D051418:Focal Adhesion Kinase 2; D010100:Oxygen